Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome

J Allergy Clin Immunol. 2011 Dec;128(6):1266-1276.e11. doi: 10.1016/j.jaci.2011.08.013. Epub 2011 Sep 14.

Abstract

Background: Stevens-Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), are life-threatening drug hypersensitivities with robust immune responses to drugs. Despite the strong HLA predisposition to drug hypersensitivities, such as HLA-B∗1502 to carbamazepine (CBZ)-induced SJS/TEN, it remains unknown whether particular T-cell receptors (TCRs) participate in recognition of small drug/peptide-HLA complexes.

Objective: Using the strong HLA predisposition in patients with CBZ-induced SJS/TEN as a model, we aimed to study the use of TCR repertoire in patients with drug hypersensitivity.

Method: We enrolled patients with CBZ-SJS/TEN, tolerant control subjects, and healthy subjects who had no history of CBZ exposure. We isolated PBMCs from the subjects, cultured CBZ-specific T cells, and globally investigated the expression level and third complementarity-determining region length distribution of the TCR profile. We further assessed the pathogenic role of the disease-specific clonotype using real-time PCR-based tests and functional analysis.

Results: On drug stimulation, CBZ-specific CD8(+) T cells were expanded in vitro and activated to release granulysin. Notably, VB-11-ISGSY was identified as the most predominant clonotype and shared among different subjects. This clonotype was present in 16 (84%) of 19 patients with SJS/TEN, absent in all 17 tolerant patients, and present at a low frequency in healthy subjects (4/29 [14%]). CBZ-specific cytotoxicity could be primed in vitro in the PBMCs of healthy subjects who are carriers of HLA-B∗1502 and VB-11-ISGSY; this cytotoxicity could be blocked by an anti-TCR-VB-11 antibody. Furthermore, a single T-cell clone expressing VA-22-FISGTY/VB-11-ISGSY showed significant cytotoxicity against HLA-B∗1502-positive antigen-presenting cells and CBZ.

Conclusion: This study establishes the key role of the TCR in the pathogenic mechanism of SJS/TEN, explains why some HLA-B∗1502 carriers are tolerant to CBZ, and provides a biomarker profile for drug hypersensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anticonvulsants / adverse effects*
  • Biomarkers / analysis
  • Carbamazepine / adverse effects*
  • Carbamazepine / immunology
  • Cell Separation
  • Cells, Cultured
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology
  • Drug Hypersensitivity / genetics*
  • Drug Hypersensitivity / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Genetic Predisposition to Disease / genetics
  • HLA Antigens / genetics
  • HLA Antigens / immunology
  • Humans
  • Male
  • Real-Time Polymerase Chain Reaction
  • Receptors, Antigen, T-Cell / genetics*
  • Receptors, Antigen, T-Cell / immunology
  • Stevens-Johnson Syndrome / chemically induced
  • Stevens-Johnson Syndrome / genetics*
  • Stevens-Johnson Syndrome / immunology
  • T-Lymphocytes / drug effects

Substances

  • Anticonvulsants
  • Biomarkers
  • Complementarity Determining Regions
  • HLA Antigens
  • Receptors, Antigen, T-Cell
  • Carbamazepine